Splenic red pulp macrophages provide a niche for CML stem cells and induce therapy resistance

Elias D Bührer; Michael A Amrein; Stefan Forster; Stephan Isringhausen; Christian M Schürch; Salil S Bhate; Tess Brodie; Joel Zindel; Deborah Stroka; Mohamad Al Sayed; César Nombela-Arrieta; Ramin Radpour; Carsten Riether; Adrian F Ochsenbein

doi:10.1038/s41375-022-01682-2

Splenic red pulp macrophages provide a niche for CML stem cells and induce therapy resistance

Leukemia. 2022 Nov;36(11):2634-2646. doi: 10.1038/s41375-022-01682-2. Epub 2022 Sep 26.

Authors

Elias D Bührer^#^{1

2

3}, Michael A Amrein^#^{1

2

3}, Stefan Forster^#^{1

2

3}, Stephan Isringhausen⁴, Christian M Schürch^{5

6

7

8}, Salil S Bhate⁶, Tess Brodie⁹, Joel Zindel⁹, Deborah Stroka⁹, Mohamad Al Sayed^{1

2}, César Nombela-Arrieta⁴, Ramin Radpour^{1

2}, Carsten Riether^{1

2}, Adrian F Ochsenbein^{10

11}

Affiliations

¹ Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
² Tumor Immunology, Department for BioMedical Research, University of Bern, Bern, Switzerland.
³ Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
⁴ Department of Medical Oncology and Hematology, University Hospital and University of Zürich, Zürich, Switzerland.
⁵ Institute of Pathology, University of Bern, Bern, Switzerland.
⁶ Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany.
⁹ Visceral Surgery, Department of BioMedical Research, University of Bern, Bern, Switzerland.
¹⁰ Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. [email protected].
¹¹ Tumor Immunology, Department for BioMedical Research, University of Bern, Bern, Switzerland. [email protected].

^# Contributed equally.

Abstract

Disease progression and relapse of chronic myeloid leukemia (CML) are caused by therapy resistant leukemia stem cells (LSCs), and cure relies on their eradication. The microenvironment in the bone marrow (BM) is known to contribute to LSC maintenance and resistance. Although leukemic infiltration of the spleen is a hallmark of CML, it is unknown whether spleen cells form a niche that maintains LSCs. Here, we demonstrate that LSCs preferentially accumulate in the spleen and contribute to disease progression. Spleen LSCs were located in the red pulp close to red pulp macrophages (RPM) in CML patients and in a murine CML model. Pharmacologic and genetic depletion of RPM reduced LSCs and decreased their cell cycling activity in the spleen. Gene expression analysis revealed enriched stemness and decreased myeloid lineage differentiation in spleen leukemic stem and progenitor cells (LSPCs). These results demonstrate that splenic RPM form a niche that maintains CML LSCs in a quiescent state, resulting in disease progression and resistance to therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Progression
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / drug therapy
Leukemia, Myeloid* / genetics
Macrophages / metabolism
Mice
Neoplastic Stem Cells / metabolism
Spleen
Tumor Microenvironment

Abstract

Publication types

MeSH terms

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